Sustained release transdermal drug delivery composition

ABSTRACT

A transdermal drug delivery system useful for the controlled, for example zero order release of one or more drugs to a selected skin area of a user, which system comprises an impervious backing sheet and a face membrane, the backing sheet and membrane secured together to form an intermediate reservoir. The face membrane is a macroporous membrane which has pores of sufficient size to avoid any rate control of the drug to be transdermally delivered to the user. The reservoir contains a viscous liquid base material selected to exude from the membrane to form a film and to occlude the skin of the user to force hydration of the stratum corneum with water from the lower layers of the epidermis of the user and a plurality of solid microparticles generally uniformly dispersed and suspended in the liquid base material. The microparticles containing an effective therapeutic amount of the drug for transdermal delivery, such as the contraceptive steroid. In use the liquid base material exuded from the macroporous membrane face forms a thermodynamically stable thin film layer in an intimate contact with the skin, while the drug is released from the microparticles into the base material and transdermally into the user.

This is a divisional of co-pending application Ser. No. 653,362, filedon Oct. 1, 1984, now U.S. Pat. No. 4,624,665.

REFERENCE TO PRIOR APPLICATIONS

This application discloses subject matter related to a prior co-pendingapplication U.S. Ser. No. 577,079, filed Feb. 6, 1984, entitledCOMPOSITE CORE COATED MICROPARTICLES AND PROCESS OF PREPARING SAME. Theprior application relates to a process for preparing coated solidmicroparticles and to the microparticles so prepared and to the use ofthe microparticles to provide for the sustained release of a drugincorporated in the microparticles. The process comprises preparing asolvent solution of an active ingredient such as a drug to beencapsulated, but more particularly a contraceptive steroid-type drugand a film-forming polymer and removing the solvent to provide a dry,composite, uniform admixture of the drug-active ingredient and thepolymer material. The mixture is then reduced to a defined, smallerparticle size distribution and the ground admixture then coated in afluidized bed with a uniform, defined wall thickness of the same orsubstantially the same film-forming polymer material used to provide thecomposite core coated microparticles. Typically, the dry compositeadmixture is reduced to a particle size of less than 1000 microns, e.g.200 microns. The film forming polymer material employed generally is apolymer, like polyvinyl alcohol or a cellulosic material or abiodegradable polymer, such as for example, a polylactide, apolyglycolide, and copolymers of lactides and glycolides. The drugemployed in the microparticles may vary, but typically may comprise forexample, a contraceptive steroid-type drug such as levonorgestrel orestradiol. For injectable compositions the particle size of themicroparticles is less than 200 microns with a uniform wall coating ofabout 0.2 to 20 microns. The microparticles are useful for thecontrolled release of a drug-active ingredient such as in a zero orderrelease pattern and for example, may be employed by injectingmicroparticles suspended in a liquid carrier into a patient.

BACKGROUND OF THE INVENTION

Transdermal delivery of medication is not a new concept, as a variety ofmedications that are readily available for delivery through the skinhave been available in ointment form for over thirty years. Withointments, however, it is difficult to achieve precise drug dosage. In atransdermal patch system, this problem is eliminated by controlling therate of drug release over a prescribed period of time. Patches are wornbehind the ear, on the chest, or the arm and dispense a drug for as longas a week at a time. For certain drugs transdermal delivery hassignificant advantages over oral administration. It eliminates "firstpass" inactivation by the liver and irregular gastric absorption.Because of constant absorption through the skin, it maintains relativelyconstant blood levels of the drugs.

Two drugs, scopolamine and nitroglycerin, have recently becomecommerically available in transdermal form. Although there aredifferences in composition and in the mechanism of drug delivery amongthe available transdermal delivery systems, they all appear to befunctionally similar. Generally the systems have essentially steadystate reservoirs sandwiched between an impervious backing and a membraneface. The systems usually are attached to the skin by an adhesive gel.Some products have a rate-controlling outer microporous membrane. Oneproduct depends on a diffusion matrix in which nitroglycerin moleculesare in equilibrium between lactose crystals and the liquid phase. Inanother product, micropockets of nitroglycerin are evenly dispersedthroughout a silicone polymer which controls the drug release rate andprevents dose dumping.

A description of the different commercial products which delivernitroglycerin transdermally is set forth by Dasta, et al., AmericanPharmacy, NS22, 2, 29-35, February 1982, which article also illustratesthe various prior art nitroglycerin patches and their construction andoperation, and which article is hereby incorporated by reference.

U.S. Pat. No. 4,336,243, issued June 22, 1982 describes transdermalnitroglycerin pads wherein the pad comprises a silicone polymer matrixbeing a crossed-linked silicone rubber having from about 10 to 200micron microseal compartments formed by the in situ cross-linking of thesilicone rubber after it is admixed with a hydrophilic solventcontaining the nitroglycerin in a hydrophobic solvent which enhances thedispersion and transport. U.S. Pat. No. 4,053,580, issued Oct. 11, 1977describes an earlier pharmaceutical delivery device employing a siliconepolymer matrix wherein the rate of release of the active ingredient iscontrolled by altering the solubility of the hydrophilic solvent systemfor the polymer matrix.

Another polymer diffusion matrix transdermal delivery system isdescribed in published European patent application 80300038.9, of A.Keith entitled Polymeric Diffusion Matrix and Method of Preparation andDrug Delivery Device Comprising Said Matrix. This application describesa polymeric diffusion matrix composed of glycerol and polyvinyl alcoholtogether with a water-soluble polymer to provide a polymer matrixcapable of sustained release of a drug dispersed in the matrix.Typically, the water-soluble polymer comprises a polyvinylpyrrolidone ora water-soluble cellulosic derivative. U.S. Pat. No. 3,797,494, issuedMar. 19, 1974 describes a transdermal bandage which includes a reservoirwith a drug confined within the interior chamber of the reservoir anddistributed throughout a reservoir matrix. In one embodiment the drug isreleased by a controlling microporous material, which microporousmaterial meters the flow of the drug into the skin at a controlled rate.In another embodiment an adhesive coating is uniformly distributedthrough microcapsules comprising a drug encapsulated with a microporousrate controlling material.

While many transdermal drug delivery systems have been described as aneconomical and effective transdermal drug delivery system particularlyfor the delivery of contraceptive steroid drugs is still needed, anddesired, particularly percutaneous delivery of steroid contraceptives ina controlled manner for periods of time ranging from one to four weeksor more.

Levonorgestrel is a synthetic steroid which has powerful progestationalactivity with minimal side effects at very low doses. Estradiol is anatural estrogen which has limited oral effectiveness because of "firstpass" inactivation during circulation. On the other hand the syntheticsteroid, ethinylestradiol, is active orally, since its inactivation bythe liver and other tissues is very low. These contraceptives and otherslike Mestranol, Norethindrone, etc., are employed in various oralcontraceptive manufactured in this country. Although levonorgestrelpills contain 150 micrograms of the drug, studies with implantable drugdelivery systems indicate that only 30 micrograms per day are sufficientto prevent fertility.

Thus, it is desirable to provide an effective transdermal drug deliverysystem for the transdermal delivery of drugs, particularly contraceptivesteroids.

SUMMARY OF THE INVENTION

The invention concerns a transdermal drug delivery system and a methodof manufacture and use of such system. In particular the inventionrelates to a transdermal drug delivery system particularly useful forthe controlled release of a contraceptive steroid drug or a combinationof such drugs.

The invention relates to a transdermal drug delivery system which may beemployed with a drug which is desired to be delivered transdermally at acontrolled or sustained rate, typically a zero order rate or otherdelivery release patterns as desired. The transdermal drug deliverysystem of the invention prevents dose dumping of the drug caused byaccidental rupture of the retaining member and ensures effective andprolonged delivery of the drug.

The invention relates to a method of and system for accelerating thetransdermal delivery of drugs into a patient by sealing the skin of thepatient with a thin layer of a viscous material to occlude the skin andtransporting a desired dosage of a drug across the thin layer typicallyfrom a rate-controlling system in contact with the thin layer. Therate-controlling system may be a thin rate-controlling membraneinterposed between the drug and the thin layer. Preferably therate-controlling system comprises microparticles of the drug or acombination of drugs to be delivered suspended in the same or similarviscous material and contained within a container system. The containersystem generally comprises a macroporous non-rate-controlling facemembrane with an impervious backing to form a pool or patch-like systemof desired face membrane area with the face of the membrane placed overand in contact with the thin occluding viscous layer on the skin. Thethin viscous layer may be coated or placed on the skin repeatedly andthe patch system placed on top of the thin viscous layer or the viscouslayer formed in situ by exudation through the membrane face when thepatch or pool system is placed in position on the skin. The patch orpool container system generally is retained in a transdermal position bythe use of a peripheral adhesive layer about the patch or pool.Typically the face or transport area of the membrane is covered prior touse by a removable cover such as a peelable strip of impervious sheetmaterial.

In another embodiment microcapsules containing a drug for delivery maybe suspended in a viscous material and the composition then spread as alayer over the skin of the user with or without a covering material.

The present drug delivery system for the transdermal delivery ofmedicaments is based on the use of solid microparticles. The systemrelease the drug from rate-controlling microparticles which aresuspended in a dermatologically acceptable viscous liquid base. Drugrelease from microcapsules is controlled by microcapsule size and wallthickness. The system is also characterized by a macroporous membranewhich delivers a thin liquid film of the base vehicle to the skin andwhose function is to deliver the drug to the skin. The function of theviscous liquid film is to occlude the skin causing the stratum corneumto swell and hydrate by forcing the diffusion of water from the lowerlayers of the epidermis an thus to accelerate the drug delivery. Thefirst phase in transdermal delivery is dependent on the rate ofdiffusion of the drug within the vehicle and its rate of release fromthe vehicle. The drug concentration in the vehicle determines thethermodynamic activity and influences the diffusion of the drug out ofthe vehicle.

The present drug delivery system suspends drug/polymer microparticles,in a delivery vehicle which microparticles control the rate of releaseof the drug to the vehicle. Drug delivery from microcapsules is zeroorder provided solid particles are present inside the microcapsule inequilibrium with a saturated solution of the drug. It is dependent onthe diffusion coefficient of the drug in the polymer, the thickness ofthe capsule wall, and the microcapsule dimensions in accordance withthis equation: ##EQU1##

Where M is the mass of the drug released, dM/dt is the steady staterelease rate at time t, DK is the membrane permeability, D is thediffusion coefficient of the drug in the membrane in cm² /sec., K is thedistribution coefficient, C is the difference in drug concentrationbetween the internal and external surface of the membrane, and r_(o)r_(i) are the outer and inner radii of the capsule wall, respectively.

Drug release from monolithic microparticles such as microspheres isfirst order and is additionally dependent on drug concentration in theparticle. Thus, the presence of the microparticles in the base vehiclehelps to maintain a constant thermodynamic activity of the drug in thevehicle by insuring that the concentration of the drug is close tosaturation.

The delivery of the vehicle to the skin is regulated by a macroporousmembrane (for example ranging from about 1 to 1000 microns) whoseproperties and pore size are selected to match those of the basevehicle. A hydrophobic membrane, for example, is best used with ahydrophobic delivery base vehicle and hydrophilic membrane with ahydrophilic vehicle while smaller micron pores e.g. 50 to 200 deliver asmaller quantity of the vehicle than larger micron pores e.g. 300 to600.

The principal barrier to permeation of small molecules through the skinis provided by the stratum corneum or "horny layer" of cells which isabout 10 to 15 microns thick. This layer is composed of a dispersion ofhydrophilic proteins in a continuous lipid matrix. The lipid componentof the layer which comprises only 20-30% of the weight of the tissue aredirectly responsible for its unique low permeability (Scheuplein, 1971).The stratum corneum may be regarded as a passive diffusion membrane,albeit not entirely inert, which follows Fick's Law in which the steadystate flux Js is: ##EQU2## where ##EQU3##

Cs=concentration difference of solute across membrane

D=average membrane diffusion coefficient for solute

S=membrane thickness

Swelling of the corneum can be produced by hygroscopic or othersubstances if they penetrate the hydrophilic zone or if lipophilicsubstances penetrate the hydrophobic zones. Increasing the state ofhydration increases the porosity and thickness of the layer andfavorably influences the transport of the drug by two to three fold. Thesimplest method for increasing hydration is to occlude the skin whichforces the diffusion of water from the lower layers of the epidermis.Estimated diffusion constant for low molecular weight nonelectrolyte is10⁻⁹ cm. sq./sec. for stratum corneum and 10⁻⁶ cm. sq./sec. for thedermis.

The degree of hydration of the stratum corneum is provided by themacroporous membrane which delivers a thin liquid film of the vehicle toits outer surface to occlude the skin. The liquid film is simultaneouslyin contact with the skin and the liquid or viscous vehicle of thereservoir through the macroporous channels of the membrane. Occlusion ofthe skin which follows may be influenced by the properties of thevehicle and the membrane.

Following topical administration of many drugs including steroids likeestrogen and norgesterone, a reservoir can form in the skin. Theexistence of this reservoir and its localization in the stratum corneumwas first proven by Vickers (1963). Much of the work in this area hasdealt with local action of drugs (e.g. hexachlorophene, sunscreens,cortisol). However, prolonged toxic response following topicaladministration of vasoconstrictors demonstrates that a cutaneousreservoir can provide sustained release into the systemic circulation.Accumulation of both estrogen and progesterone in subcutaneous tissueand underlying muscle has been observed and is more pronounced withpercutaneous than with subcutaneous administration. The duration of thelocal reservoir appears to be dependent on the normal 14 day cycle ofepidermal turnover. Irritation with a detergent or methotrexateincreases turnover and can reduce the duration of the reservoir bynearly 50%. Inhibition of turnover with fluorinated steroids can doublethe duration to 28 days. In addition a compound which very rapidlypenetrates and diffuses is maintained in the reservoir for a shortperiod of time (e.g. nicotine, 3-4 days). Since occlusion of the area ofapplication appears necessary to promote sustained absorption from thereservoir, continued absorption following removal of the delivery systemshould be minimal unless the concentration is very high.

Pronounced and prolonged effects of estrogens and gestagens can beexpected by the transdermal route since it is the total amount ofhormone absorbed by the body that is decisive, and not the peak heightof the hormone level. The flux rate of steroids through human skin hasbeen studied by others and are shown below Table 1.

                  TABLE 1                                                         ______________________________________                                        FLUX RATES OF STEROIDS                                                                  FLUX (MOLES/CM.sup.2 HR).                                           STEROID     (Feldman 1969)                                                                              (SCHAEFER 1979)                                     ______________________________________                                        17β estradiol                                                                        8.2 × 10.sup.-11                                                                      5.8 × 10.sup.-10                              17β estradiol        4.6 × 10.sup.-10                              Testosterone                                                                                5 × 10.sup.-11                                                                        1 × 10.sup.-9                               Estriol                   7.8 × 10.sup.-11                              Progesterone                                                                              3.4 × 10.sup.-11                                            Hydrocortisone                                                                            2.5 × 10.sup.-11                                            Corticosterone                                                                            7.5 × 10.sup.-12                                            ______________________________________                                    

Table 1 shows that the flux rates of estradiol and progesterone arefairly high in comparison to the corticosterones. These flux ratesdepend on the concentration of the applied substance in the vehicle. Atlow concentrations the rates are proportional to the concentration inthe vehicle. This proportionality is not 1 to 1 since a doubling of theconcentration increases the flux by about 30-50%.

This general pattern of regional variation was found to hold for otherchemical moieties (steroids, pesticides, and antimicrobials). Althoughthe stratum corneum is generally accepted to be the major barrier topercutaneous penetration, this appears to hold only if the skin isintact. Damage to the stratum corneum makes the other layers function asbarriers. For example, the penetration of hydrocortisone throughmodified skin results in a tenfold increase in the penetration ofhydrocortisone from 1% to 10% when the skin is occluded. The thin liquidfilm which is exuded by the macroporous membrane occludes the skin toincrease drug penetration.

The drug delivery system of the invention is based on the use of drugpolymer solid microparticles or rate-controlling microcapsules which aresuspended in a dermatologically acceptable viscous liquid base materialor vehicle. The base is separated from the skin by a non drug nonrate-controlling macroporous membrane. The outer rim or perimeter of themembrane is covered by a nonsensitizing hypoallergenic adhesive layer orother means to secure the system to the skin which holds the microporousmembrane in contact or adjacent to the skin and prevents loss of thedrug to the surrounding area. The microcapsules release the drug to thebase in a controlled release pattern and maintains it in athermodynamically stable condition. Release is controlled by theselected microcapsule size and thickness of the microcapsule wall. Thus,controlled release is obtained and the presence of the microcapsulesprevents dose dumping caused by accidental rupture of the retainingmembrane and ensures a prolonged delivery of the drug.

An important feature of the drug delivery system in this embodiment isthe macroporous retaining membrane which separates the liquid base fromskin. This membrane delivers a thin film controlled amount of the basematerial to its outer face surface to contact the skin. The liquid filmoccludes the skin and forces hydration of the stratum corneum with waterfrom the lower layers of the epidermis. This in turn acceleratesdelivery of the drug, e.g. steroids across the stratum corneum. Intimatecontact between the skin and the thermodynamically stable viscous liquidbase also ensures uniform delivery of the drug throughout the treatmentperiod. Unlike microporous membranes, the macroporous membrane does notcontrol the rate of drug delivery to the skin, but solely the amount andthickness of the film of liquid material in contact with the skin.

The macroporous membrane ensures the presence of a continuousdrug-filled liquid base pathway between the viscous base reservoir andthe skin. The dimensions of the macropores and the degree ofhydrophobicity of the membrane are selected to match the properties ofthe liquid base (i.e. viscosity, hydrophobicity). The function of themacroporous membrane is to permit only a small, but sufficient quantityof the base material to pass through the pores to the skin surfacewithout being messy or leaky.

Microparticles are suspended in the liquid base material to provide athermodynamically stable base with a constant driving force of the drugin the liquid base. The microparticles or microspheres suspended in theliquid base material comprise solid mixtures of the drug in a polymerand one embodiment may comprise the microparticles as described in theassignee's co-pending application Ser. No. 577,079 (hereby incorporatedby reference).

The transdermal drug delivery system of the invention usually includesan impervious backing sheet with a macroporous face membrane, thebacking sheet and the macroporous membrane typically secured togethergenerally along its edges to form an intermediate layer-like reservoirtherebetween. The macroporous membrane has pores of sufficient size toavoid rate control of the active drug ingredient to be transdermallydelivered, but of a the size sufficient to permit the liquid basematerial to be exuded therefrom so as to form a thin film of the basematerial for intimate contact with the skin of the user adjacent theface of the macroporous membrane.

The reservoir comprises a dermatologically-acceptable, generally viscousliquid base material, the viscosity should be sufficiently high tosuspend the microparticles therein and to prevent leakage or excessiveflow through the membrane pores, but low engough to permit the functionof the thin film on the skin. A plurality of solid microparticles ormicrospheres are generally uniformly dispersed and suspended in theliquid base material within the reservoir. The microparticles include aneffective therapeutic amount of an active drug ingredient or acombination thereof, such as a contraceptive steroid, likelevonorgestrel or estradiol or a combination thereof for transdermaldelivery for a particular therapeutic purpose such as contraception. Thedrug is present in an effective therapeutic amount within themicroparticles suspended in the reservoir with the microparticlesgenerally designed to provide for a zero order release of the activedrug material. Preferably, the microparticles are composed of anadmixture of a polymer with the active drug ingredient in themicroparticles varying as desired, but generally from about 0.1 to 30percent by weight, for example, 1 to 20 percent and wherein themicroparticle has a thin polymer wall coating thereon such as a wallcoating imparted in a fluid bed coating system or by other means.Typically an adhesive layer is placed about the periphery of the drugdelivery system and usually an impermeable material such as a protectivepeel strip is secured to the open face of the macroporous membrane,which peel strip is to be removed just prior to use.

In use and on removing of the peel strip, the drug delivery system inthe form of a patch is applied to the skin of the user at a desirablelocation and the patch adhered by an adhesive exposed after removal ofthe peel strip. The macroporous nature of the membrane permits theviscous liquid base material in the reservoir to exude through themacropores to form a thin film on the face of the macroporous membraneand place the macroporous membrane in intimate contact with the skin ofthe user thus forming a thin dynamically stable thin film. The activedrug ingredient is released at a selected zero order rate from theplurality of microparticles suspended in the liquid material; andtherefore, transported directly through the viscous liquid base materialinto the skin of the user. The drug delivery system of the inventioncontributes significantly to the accelerated permeation of the drugthrough the skin, since the skin is continuously in contact with thedrug in solution. Further, since the skin is occluded to permithydration of water from the lower layers, the permeation of the drugfrom the liquid base material into the hydrated stratum corneum is muchfaster than when a dry dehydrated corneum is presented. In addition, theskin is continuously in contact with the viscous liquid base materialwhich is generally selected to have emollient properties. This emollientcontributes to the accelerates delivery by maintaining the outer skinsoftness and pliability to assure continuous contact between the skin,the liquid base material and the membrane surface which is in quite acontrast to contact with a dry solid matrix of the prior art.

The drug polymer microparticles produce a thermodynamically stableliquid base as a source of the active drug and practically eliminatesthe problem of drug dose dumping if the membrane is accidentallyruptured as with prior art transdermal drug delivery systems. The rateof drug delivery may be modified and tailored by several variables, suchas the microparticle size, composition, polymer composition, wallthickness, and the macroporous membrane properties and porosity and theselection of the viscous liquid base composition and properties as tothe degree of hydrophilicity or hydrophobicity. The various additivesmay be compounded and added into the liquid base material, whichcompounds may be employed to impart special properties to the liquidbase material; for example, to enhance diffusion, control steroidreservoir formation, improve antiseptic properties, reduce infection,control viscosity, or to add emollient or lubricant properties whereprolonged usage of the transdermal drug delivery system is desired.

The liquid base material may comprise a variety of materials, buttypically should be a viscous-type liquid material capable of suspendingthe plurality of solid microparticles therein and also to be exudedthrough the selected pores of the macroporous membrane so as to form athin stable thermodynamic film on the skin of the user. The liquid basematerial should be dermatologically acceptable to the user. Theviscosity of the liquid base material should be high enough so that theliquid base material will not run from the macropores of the macroporousmembranes and deplete the reservoir or become messy to the user, and yetnot high enough to prevent the liquid base material from entering thepores and forming the thin film on the skin of the user after aprotective face layer has been peeled away from the outer face of themacroporous membrane. Typically, the liquid base material should have agel or grease-like viscosity and properties.

The liquid base material should be selected to be compatible with and topermit the transport of the drug within the microparticles. Typically,if the drug is a low water soluble-type drug then the liquid basematerial would be a low water soluble base material generally matchingthe hydrophobicity of the drug and vice versa where the drug is watersoluble, the liquid base material may be selected to be also watersoluble so that there is transport and compatibility from the drugrelease through the wall of the microparticle and so the drug may moveeffectively through the liquid base material in the reservoir and ontothe thin film adjacent the user directly into the skin of the user. Forexample, the liquid base material may comprise a hydrophobic materialsuch as a long chain, e.g. C₈ -C₂₂ hydrocarbon-type materialparticularly for use with water-insoluble or very low water solubledrugs, such as for example, a grease-like hydrocarbon such as apetroleum based jelly e.g. Vaseline, a semisolid mixture of hydrocarbonshaving a mp of 38°-60° C. The liquid base material may comprise also ahydrophilic-type material such as a polyethylene glycol, glycerol, or awater solution placed in a gel-like form through the use of viscositymodifying additive or gel-like material such as polyvinylpyrrolidone,agar, proteins, thickeners and the like. In addition, it should be notedthat the liquid base material in the reservoir may contain othermodifying additives to impart other desirable properties, such as theuse of emollients such as glycols like glycerine, viscosity controllingagents, preservatives, thickening agents, antibacterial agents, such asa quaternary ammonium compound, stabilizers, depletion indicatingdevices such as dyes, waxes and other material typically employed inpharmaceutical and cosmetic applications and which are dermatologicallyand pharmaceutically acceptable.

The macroporous membrane material comprises a sheet material havingpores to permit the passage of the viscous liquid base material. Thefunction of the membrane is merely to contain the viscous liquid withinthe reservoir and to permit a thin film to be formed on the face side ofthe membrane. The macroporous membrane may be formed of a variety ofmaterial either synthetic or natural polymeric material, but typically amembrane material as used in the prior art, such as for example, of acellulosic material, an ethylenevinyl acetate copolymer material,cellulose acetate material, vinyl halides, polyvinyl chloride, nylon,porous polyolefins such as polyethylene, polypropylene and fluorocarbonsand other materials which are adapted to be formed with or have pores ofcontrolled size.

The microparticles employed in the drug delivery system generallycomprise solid microparticles wherein the core of the particle containsan admixture of a polymer together with one or more of the drugs whichare to be delivered by the microparticles, the active ingredient in thecore may comprise a varying amount and range for example from 5 to 95percent by weight, such as 20 to 80 percent by weight with the remaindermade up a core polymer material. The amount of microparticles in thebase material may vary and range from 5 to 70 percent, e.g. 10-30percent by volume of the reservoir material. The microparticle comprisesand has a wall thickness of generally the same or similar polymer as thecore material. The core material, of course, may have other additives,such as binders, adhesives, fillers and the like. The microparticles mayhave a wall coating produced by coating of the solution in a fluidizedbed to provide a generally uniform wall thickness.

The active drug ingredient may comprise a wide variety of materials orcombinations and be selected for the particular therapeutic functiondesired to be transdermally released. Preferably, the active drugingredient does not react with and is chemically inert with the liquidbase material and with the synthetic film forming polymer materialcomprising the microparticle. The microparticle is generally less than1000 microns and typically less than about 200 microns. Themicroparticles may comprise microspheres and the microparticles designedto deliver a constant and sustained dose of the active ingredient forperiods ranging from several hours to several years; for example, oneday to one month. In one embodiment the control release rate may be azero order release rate. The microparticles may be formed of natural orsynthetic polymeric materials both of the core material and the coatingmaterial and particularly with biodegradable polymers such as thelactides, glycolides, or copolymers of lactide and glycolide asbiodegradable polymers. For example, in one embodiment microparticlesmay be prepared from employing an active drug steroid such aslevonorgestrel or estradiol and combinations in admixture with abiodegradable (polylactide) polymer and then coated with a biodegradable(polylactide) polymer to prepare the microparticles.

The drug material to be used as the active ingredient may vary andcomprise for example, antibiotics, antibacterial agents, hormones,steroids, or other therapeutic agents. However, the principles of thedrug delivery system will be illustrated employing a contraceptivesteroid hormone with a drug delivery system designed to provide forsustained release by transdermal delivery of a contraceptive hormonesuch as levonorgestrel or estradiol. The sustained release of the drugfrom the microcapsules should be such as for an effective amount to betransdermally delivered to the user in an amount to be effective for thepurpose for which the drug is selected. For example, with contraceptivesteroid hormones approximately 5 to 150 micrograms per day per user andgenerally 20 to 50 micrograms per day is sufficient to prevent femalefertility when using a levonorgestrel drug as an active ingredient.

The drug delivery system may be in the form of a patch or bandage andwherein the face of the macroporous membrane in contact with the skinthrough the thin thermodynamically liquid layer may range as desireddepended upon the transport mechanism and rate, but typically wouldrange from about 1 to 30 square centimeters, and more typically 2 to 10square centimeters.

The invention will be described for the purposes of illustration only inconnection with certain embodiments; however, it is recognized thatvarious changes, modifications, additions, and improvements may be madeto the illustrated embodiments by a person skilled in the art allfalling within the spirit and scope of the invention.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a schematic, sectional, illustrative view of the drug deliverypatch system of the invention;

FIG. 2 is a schematic, sectional, and illustrative view of the patchdelivery system of FIG. 1 as applied to the skin of a user; and

FIGS. 3(a and b) is a graphical representation of the comparison of invitro release and plasma levels of levonorgestrel from microcapsules.

DESCRIPTION OF THE EMBODIMENTS

FIGS. 1 and 2 show a bandage-type transdermal sustained release deliverysystem of the invention 10 wherein the device comprises an imperviousbacking sheet 12 and a macroporous face membrane 14 containing aplurality of macropores generally having a pore size of 200 to 500microns and composed of an ethylene vinyl acetate copolymer. The backingsheet 12 and the macroporous membrane 14 form a generally flat reservoir16 therebetween, the reservoir containing a viscous liquid base material18 such as a viscous hydrocarbon vehicle like Vaseline. Uniformlysuspended in the hydrocarbon of liquid viscous base there are aplurality of solid microparticles 20 containing, for example,levonorgestrel in an amount to deliver about 30 micrograms per day ofthe levonorgestrel from the microparticles in a zero order release overa period of one to four weeks. The microparticles 20; for example, thoseas prepared in the co-pending application generally comprise from about5 to 75 percent by weight of the viscous liquid base material within thereservoir 16, e.g. 20 to 60 percent. Arround the peripheral edge of thebacking material is an adhesive layer 22 while a removable peel strip 24against the face of the macroporous membrane 14 prevents the dischargeof the viscous liquid base material prior to use.

FIG. 2 shows the application of the bandage-type delivery system to theskin of a user 26 and illustrates that a thin liquid film 28 of theviscous liquid 18 in the reservoir 16 forms across the entire face ofthe macroporous membrane 14 to maintain intimate contact between theface of the macroporous membrane 14 in the skin 26 and to accelerate thetransdermal delivery of the drug from the microcapsules 20.

A typical sustained release for the release of levonorgestrel is: a 9.4square centimeter of Johnson and Johnson Rayon™ First AidTape-Hypo-Allergenic - 1 inch wide, 1.5 inch long for the imperviousbacking and to form the adhesive layer and a 2 square centimeter ID -2.25 square centimeter OD - 2/3 mm thick teflon ring. The macroporousmembrane may comprise 4.9 square centimeter Millipore Corp. F/LW 025Fluoropore (PTFE) porous membrane - pore size 2.0 μm, means thickness200 μm, typical porosity 85 percent, hydrophobic material. Microspheresare prepared from the levonorgestrel and the poly-L(-)lactide asfollows: Prepare a 2.5 percent wt/v solution of polyvinyl alcohol (PVA)#523 in one liter of distilled water; prepared a 15 percent wt/vsolution of poly-L-(-)lactide, approx. 1 R.S.V. in 300 ml of reagentgrade methylene chloride; mix 5 ml of the poly-L-(-)lactide solution, 10ml methylene chloride and 5 grams of levonorgestrel to form a uniformslurry; take the 1 l of PVA solution and pour it into a 2 l stainlesssteel beaker. Stir at approx. 1000 RPM (1550×0.7) and heat at lowtemperature, (approx. 35° C.); add levonorgestrel slurry. Heat approx. 4hours, then turn off heat and stirrer; wet sieve off the 45-106 μm sizefraction; and dry in vacuum oven at room temperature and recover thesolid microspheres. Then 45 mg of these solid microspheres are mixedwith 85 mg of Vaseline or a viscous vehicle (trademark ofChesebrough-Pond's, Inc.). The Teflon ring is placed in the center onthe adhesive side of the tape and the Vaseline mixture is then spread touniform thickness iside the Teflon ring. The porous membrane is thenplaced over the mixture of Vaseline to form a complete patch. Anestradiol patch is similar prepared using 70 mg of Vaseline with 38 mgof microspheres containing estradiol.

FIG. 3(a) illustrates an in vitro sustained release of levonorgestrelfrom a microparticle wherein the drug comprises about 10 percent of themicroparticles and the biodegradable polymer of polylactide comprisesabout 90 percent by weight of the core material and wherein the wallthickness of the microparticle ranges from about 3 to 8 microns and iscomposed of the polylactide polymer.

FIG. 3(b) illustrates the in in vivo release of the hormonelevonorgestrel into blood plasma of rabbits from the same microparticlesas in FIG. 3(a). Thus, it is illustrated that the levonorgestrelmicrocapsules provide for a sustained generally zero order release ofthe contraceptive.

A transdermal delivery system known as DermaPatch has been developedwhich delivers levonorgestrel across freshly excised mouse skin at adose of 43 micrograms/day from a 2.4 square centimeter patch. Drugrelease is sustained at a constant rate over a minimum period of 14days. A system which delivers estradiol across freshly excised mouseskin at a dose of 5 micrograms/day from a 2.4 square centimeter patchhas also been developed. A combined contraceptive system wouldconstitute 20 micrograms/day of levonorgestrel, and 25 micrograms/day ofestradiol over a period of 3-7 days which target doses can be deliveredfrom a single 5-6 square centimeter patch system which contains bothsteroids.

In Vitro mouse skin permeation studies were conducted with a 2.4 squarecentimeter patch which was placed in a 20 mm diameter water jackettedFranz diffusion cell mounted on a 9-cell Drive Unit/Mounting Assembly.The water jacket temperature of the cells was controlled by a bath andwater circulator which is maintained at 37° C. This system is widelyused in the pharmaceutical industry for measuring the permeability ofpercutaneous patches across animal and cadaver skins. The preliminarystudies with levonorgestrel and estradiol it was discovered that thesize of the cell reservoir was too small to permit overnight studiesbecause the solution became saturated rapidly with the steroids within afew hours after startup so an adaptor was used for the UniversalDiffusion Cell to permit overnight studies.

Release of each drug was determined as a function of time by analysis ofaliquots of the contents of the reservoir in a Water High PressureLiquid Chromatograph (HPLC) using a u Bondpak C-18 radial pack columnwith a mobile phase of 60% ethanol in water. The steroids were measuredin a uv detector at a wavelength of 280 nm for estradiol and 254 forlevonorgestrel.

Pieces of full thickness abdominal skin were freshly excised from a 6week old male nude mice and mounted individually on the Franz diffusioncell. Before use, the skins were washed three times in 200 ml normalsaline to remove extraneous and other soluble material. The facemembrane of the system was applied to the stratum corneum side of theskin. The skin permeation profile of each drug was followed by removingthe liquid from the receptor compartment for assay at the appropriateintervals. The compartment was then filled with fresh saline and thepermeation continued. Release of the drug was monitored in a liquidchromatograph (HPLC).

The results of the skin permeation studies indicated that levonorgestrelpenetrates the abdominal skin of the nude mouse at a zero order rate.The rate of skin permeation for levonorgestrel delivered by the systemduring 24 hours is approximately 43 μg/day. The area of the membrane incontact with the skin was 2.4 square centimeters. This translates into askin permeation rate of 1.8 μg/square centimeter/hour or 18 μg/squarecentimeter/day. This rate continued for a period of 14 days.

Table 2 summarizes the test data on levonorgestrel and estradiol mouseskin permeation tests:

                  TABLE 2                                                         ______________________________________                                        LEVONORGESTREL       ESTRADIOL                                                Micrograms/2.4 sq. cm.                                                                      Days   Micrograms/2.4 sq. cm.                                                                        Days                                     ______________________________________                                        about    25       1       6            1                                               90       2      10            2                                              140       3      16            3                                              270       7                                                                   375       8                                                                   405       9                                                                   570       10                                                                  505       11                                                                  590       14                                                          ______________________________________                                    

To obtain maximum flux rates aliquots of the reservoir were analyzedduring a period of 8 hours on day 2, day 3, and day 7. The results showzero order release of the hormone from the system on each of the threedays at an average rate of 6.7 micrograms per hour (160 micrograms perday/2.4 square/centimeters). Thus a patch with a surface area of 0.5square centimeters should be capable of delivering 20 micrograms per dayof levonorgestrel.

Tests were also conducted with an estradiol-containing patch system withthe 2.4 square centimeter estradiol patch, and permeation rates of 5 perday were achieved. At this rate a patch with a surface area of 5 squarecentimeters would be capable of delivering 2.5 milligrams per day oflevonorgestrel.

Table 3 sets forth the properties of a patch-type sustained releasesystem:

                  TABLE 3                                                         ______________________________________                                        PROPERTIES OF DERMAPATCH ™ SUSTAINED                                       RELEASE SYSTEM                                                                              LEVON-                                                                        ORGESTREL ESTRADIOL                                             ______________________________________                                        SYSTEM                                                                        CHARACTERISTICS                                                               Surface area, sq. cm.                                                                         2.4         2.4                                               Loading dose, mg.                                                                             31          32.6                                              MOUSE SKIN                                                                    PERMEATION                                                                    Rate of permeation                                                                            0.75-2.8    >0.09*                                            mcg./sq. cm./hr.                                                              Minimum dose absorbed,                                                                         43-160     >5.2*                                             mcg./24 hr.                                                                   Period permeation studied,                                                                    14          3                                                 days                                                                          ESTIMATED PATCH                                                               SIZE REQUIRED                                                                 Dose required, mcg./day                                                                       20          25                                                Estimated size needed to                                                                      0.5         5                                                 deliver required dose, sq.                                                    cm.                                                                           Expected duration, days                                                                       >7          >7                                                ______________________________________                                         *These are minimum values which have not been corrected for saturation        effects. It is expected that the maximum flux rates will be nearly 2-3        times greater.                                                           

LIST OF REFERENCES

Dasta, et al., American Pharmacy, NS22, 2, 29-35, Feb. 1982.

Feldman, R. J. and Maibach, H. I., J. Invest. Derm. 52, 89 (1969).

Schaefer, H., Stuttgen, G. and Schalla, W., Contraception via TopicalApplication? - A Review - , Contraception, 20 (3), 225 (1979).

Scheuplein, R. J. and Blank, I. H., Permeability of the Skin, Physiol.Rev., 51, 702 (1971).

Vickers, C. F. H., Arch. Dermatol. 88, 20-25 (1963).

What is claimed is:
 1. A composition for the accelerated sustainedrelease, transdermal delivery of a drug to a user, which compositioncomprises:(a) a viscous, film-forming base material selected to matchgenerally the degree of hydrophobicity of the drug and, when placed incontact with the skin of the user, to occlude the skin of the user andto force hydration of the stratum corneum layer by diffusion of waterfrom the lower layers of the epidermis of the user in use and toincrease the porosity of the stratum corneum layer and thereby toaccelerate the transdermal drug delivery across said layer; and (b) aplurality of drug rate controlling solid microparticles generallyuniformly dispersed and suspended in the base material, themicroparticles having a particle size of less than 1000 microns andcontaining an effective therapeutic amount of a drug for transdermaldelivery, the active drug of transdermal delivery and the base materialselected to permit the transport of the drug from the rate controllingmicroparticles and through the base material and into the skin of theuser;whereby, on application to the skin of the user of the transdermaldrug composition, the drug is released at a sustained release rate fromthe suspended microparticles into the base material and into the skin ofthe user.
 2. The composition of claim 1 wherein the base materialcomprises a viscous hydrocarbon, and the drug comprises awater-insoluble drug.
 3. The composition of claim 1 wherein the basematerial comprises a viscous hydrocarbon, and the drug comprises ahydrocarbon-soluble contraceptive steroid.
 4. The composition of claim 1wherein the microparticles comprise a biodegradable polymer admixed withthe drug, and the microparticles contain a thin outer coating layer of abiodegradable polymer.
 5. The composition of claim 1 wherein the basematerial comprises a glycerol water-containing base material, andwherein the drug to be transdermally delivered comprises a water-solubledrug.
 6. The composition of claim 1 wherein the drug comprises:norethindrone, norgestrel, estradiol, levonorgestrel, mestranol, andcombinations thereof.
 7. The composition of claim 1 wherein the basematerial comprises a viscous hydrocarbon material having a melting pointof 38° C. to 60° C.
 8. The composition of claim 1 wherein themicroparticle comprises a microparticle having a particle size of about200 microns of less, wherein the active ingredient comprises alevonorgestrel or estradiol, wherein the active drug is admixed with alactide or glycolide polymer, and wherein the microparticle has a wallthickness composed of a lactide or glycolide polymer.
 9. The compositionof claim 1 wherein the microparticles comprise from about 5 to 75percent by weight of the base material.
 10. The composition of claim 6wherein the sustained release rate comprise a zero order release rate atabout 5 to 150 micrograms per day.
 11. The composition of claim 1wherein the drug comprises from about 0.1 to 30 percent by weight of themicroparticle.
 12. The composition of claim 1 wherein the microparticleshave a uniform outer wall coating of about 0.2 to 20 microns.
 13. Thecomposition of claim 1 wherein the concentration of the drug in the basematerial is close to saturation.
 14. The composition of claim 1 whereinthe microparticles comprise an admixture of the drug and a polymer toform an inner core and the microparticle include a thin outer polymercoating layer.
 15. The composition of claim 14 wherein the outer polymercoating layer comprises a polymer which is the same or essentially thesame as the polymer admixed with the drug.
 16. A composition for theaccelerated transdermal sustained release delivery of a drug to a user,which composition comprises:(a) a viscous, film-forming, hydrocarbonbase material having a melting point of 38° C. to 60° C. selected whenplaced in contact with the skin of the user, to occlude the skin of theuser and to force hydration of the stratum corneum layer with water fromthe lower layers of the epidermis of the user in use and thereby toaccelerate drug delivery; and (b) a plurality of drug rate controllingsolid microparticles generally uniformly dispersed and suspended in thebase material and the containing an effective therapeutic amount of asteroid drug for transdermal delivery, the active drug material fortransdermal delivery and the base material selected to permit thetransport of the drug through the walls of the microparticles and thebase material and into the skin of the user, and wherein themicroparticles comprise a biodegradable polymer admixed with the drug,and the microparticles contain a thin outer coating layer of abiodegradable polymer;whereby, on application to the skin of the user ofthe transdermal drug composition, the drug is released at a accelerated,sustained release rate from the suspended microparticles into the basematerial and into the skin of the user.
 17. The composition of claim 16wherein the microparticles have a particle size of 200 microns or less.